Gangliosides are neuraminic acid-containing glycosphingolipids that accumulate in the outer leaflet of plasma membranes. Gangliosides such as GD2 and GD3 are prevalent tumor markers. They are expressed in neuroblastoma, melanoma, small cell lung cancer and gliomas (Hakomori, 1996, Cancer Research, 56: 5309) as well as breast cancer stem cells (Battula et al., 2012, The Journal of clinical investigations, 122: 2066), but they are absent in normal cells. Hence, GD2 and GD3 have been exploited as tumor targets, and they are validated clinical targets. Partial therapy can be achieved by passively administering purified anti-GD2 (Cheung et al., 1987, J Clin Oncol, 5: 1430) or anti-GD3 monoclonal antibodies (mAbs) (Houghton et al., 1985, Proc Natl Acad Sci USA, 82: 1242). However, passive immunity has high financial cost, significant side effects, limited frequency of intervention, and low therapeutic efficacy (Navid et al., 2010, Current Cancer Drug Targets, 10: 200).
As an alternative, many groups have pursued active immunotherapy gangliosides (Astronomo and Burton, 2010, Nat Rev Drug Discov, 9: 308). However, serious difficulties associated with gangliosides include poor immunogenicity, poor solubility and poor formulations, limited access and difficulty to prepare well-characterized and homogeneous immunogens, and the potential of poor selectivity with the risk of cross-reactivity to non-tumor gangliosides that are highly related in structure.
For example, a GD2 lactone chemically conjugated to keyhole limpet hemocyanin (KLH) is immunogenic, and can induce antibodies that delay tumor growth in mice (Chapman et al., 2000, Clinical Cancer Research, 6: 4658). The antibodies induced by this vaccine act through a complement-dependent cytotoxicity (CDC) mechanism (Kim et al., 2011, Cancer Immunology, Immunotherapy, 60: 621). However, the KLH-ganglioside conjugation yields chemically heterogeneous products (Danieshefsky and Allen, 2000, Angew Chem Int Ed, 39: 836), which is a serious drawback. Other ganglioside conjugates have shown poor immunogenicity and generally elicited a low and transient anti-ganglioside antibody response (Ragupathi et al., 2000, International Journal of Cancer, 85: 659). Even the most immunogenic ganglioside, a GM2-KLH vaccine did not provide clinical benefits (Kirkwood et al., 2001, Journal of Clinical Oncology, 19: 2370) and was discontinued. Additional experimental approaches include GD2-peptide mimotopes (Wondimu et al., 2008, Cancer Immunology, Immunotherapy, 57: 1079), GD2-mimicking peptides (Bolesta et al., 2005, Cancer Research, 65: 3410), and GD2 mimotope DNA vaccines (Zeytin et al., 2000, Cancer Gene Therapy, 7: 1426) that can induce cross-reactive immunity to GD2. However, immune responses were not very effective at protecting the host in tumor-therapy paradigms (Bleeke et al., 2009, European Journal of Cancer, 45: 2915).
There is thus still a need to be provided with a new therapeutic approach using gangliosides as targets.